ORGANIC LETTERS
Asymmetric Synthesis of the Chlorocyclopropane-Containing Callipeltoside A Side Chain
2001 Vol. 3, No. 4 503-505
David A. Evans* and Jason D. Burch Department of Chemistry & Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
[email protected] Received January 5, 2001
ABSTRACT
The callipeltoside A chlorocyclopropyl-containing dienyne side chain has been synthesized in nine steps and 33% overall yield from commercially available 1,2,5,6-O-dicyclohexylidene-D-mannitol. The key steps in the synthesis are a highly diastereoselective cyclopropanation of a vinyl chloride allylic ether and a Suzuki cross-coupling to complete the carbon framework.
During the course of screening marine organisms for the identification of new antitumor and antiviral agents, Minale and co-workers isolated the active constituent, callipeltoside A (1, Figure 1), from the marine sponge Callipelta sp. This new macrolide was found to display antitumor activity, as well as in vitro protection of HIV infected cells.1 Callipeltoside A contains a highly functionalized deoxyamino sugar (callipeltose) and a dienyne-trans-chlorocyclopropane side chain appended to a polyketide-derived 14-membered macrolactone. The stereochemical assignment of 1 was made on
(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (b) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C. Tetrahedron 1997, 53, 3243-3248. (2) (a) Smith, G. R.; Finley, J. J.; IV.; Giuliano, R. M. Carbohydr. Res. 1998, 308, 223-227. (b) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169171. (c) Vela´zquez, F.; Olivo, H. F. Org. Lett. 2000, 2, 1931-1933. (d) Olivo, H. F.; Vela´zquez, F.; Trevisan, H. C. Org. Lett. 2000, 2, 40554058.
Figure 1. 10.1021/ol0155182 CCC: $20.00 Published on Web 01/31/2001
the basis of extensive NMR spectroscopic studies. At the present time, the principal stereochemical ambiguity yet to be addressed is associated with the absolute stereochemical relationships associated with the pendant cyclopropane ring. The unique structure and biological activity of callipeltoside A has stimulated efforts directed toward a synthesis and ultimate stereochemical assignment of this natural product.2 In this Letter we describe a practical asymmetric synthesis of the chlorocyclopropane-containing dienyne side chain. Scheme 1 illustrates the general synthetic strategy that is being pursued in the assemblage of callipeltoside A. Because of the stereochemical ambiguity associated with the dienyne side chain, our objectives are to be able to readily access either C15-C22 side chain enantiomer which might be appended to the glycosylated macrolactone through an (E)selective Horner-Emmons coupling of phosphonate 4 with the lactone subunit 3.3 Dibromoolefin 5 serves as a suitable precursor to phosphonate 4 using either a Stille4 or a Suzuki5 coupling/elimination sequence. The chlorocyclopropane 5
© 2001 American Chemical Society
Scheme 1
adopted. Homologation of unpurified 10 using Ohira’s reagent 128 yielded alkyne 11 in 94% yield. The one-pot hydroboration/chlorination sequence developed by Masuda9 was then employed to afford vinyl chloride (+)-8 in 70% yield as a single olefin isomer (>20:1). Vinyl chloride (+)-8 proved resistant to Simmons-Smith cyclopropanation. Less than 15% conversion was observed using either the Furukawa10 or Denmark11 reaction variants. These failures prompted investigation of the highly activated conditions developed by Shi, in which Et2Zn is premixed with 1 equiv of trifluoroacetic acid prior to the addition of 1 equiv of CH2I2.12 This dramatically enhanced carbenoid delivered chlorocyclopropane 13 as a single diastereomer (>50:1)13 in 82% yield (Scheme 3). This result illustrates
Scheme 3
would arise from a diastereoselective cyclopropanation of vinyl chloride 8. While the Takai reaction6 of glyceraldehyde cyclohexylidene ketal 107 was initially investigated to afford vinyl chloride (+)-8, the reaction exhibited modest selectivity (87: 13) and yields (Scheme 2). Significantly, the olefin isomers
Scheme 2
Reaction conditions: (a) KIO4, KHCO3, THF/H2O, rt; (b) CrCl2, CHCl3, THF, 70 °C; (c) 12, K2CO3, MeOH, rt; (d) (i) Thexyl2BH, -15 to 0 °C, THF, (ii) CuCl2, H2O, HMPA, THF, 0 to 70 °C.
were not readily separated by chromatography. As an alternative, an improved two-step stereospecific route was (3) (a) Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am. Chem. Soc. 1984, 106, 3548-3551. (b) Nicolaou, K. C.; Chung, Y. S.; Hernandez, P. E.; Taffer, I. M.; Zipkin, R. E. Tetrahedron Lett. 1986, 27, 1881-1882. (c) Nicolaou K. C.; Webber, S. E. Chem. Commun. 1986, 1816-1817. (4) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-8879. (5) (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990, 31, 6509-6512. (b) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691-2694. 504
Reaction conditions: (a) Et2Zn, CF3COOH, CH2I2, CH2Cl2, rt; (b) Dowex resin, MeOH, rt; (c) Pb(OAc)4, K2CO3, CH2Cl2, rt; (d) PPh3, CBr4, CH2Cl2, rt.
that the Shi conditions can be used for directed cyclopropanations of electron-deficient olefins. Removal of the cyclohexylidene protecting group initially proved difficult due to reketalization during in vacuo concentration. However, washing the methanolic reaction solution with hexanes prior to concentration removed the cyclohexanone dimethyl ketal and allowed the isolation of diol 14 in 84% yield (Scheme 3). Diol 14 was converted to the desired dibromide (-)-5 in two steps (Scheme 3). Diol cleavage with potassium carbonate-buffered lead tetraacetate afforded the volatile aldehyde 16 which was treated with 5 equiv of the Corey-Fuchs reagent14 without purification to (6) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 74087410. (7) Aldehyde 10 was prepared by the method of: Schmid, C.; Bradley, D. A. Synthesis 1992, 587-590. (8) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522. (9) Masuda, Y.; Hoshi, M.; Arase, A. J. Chem. Soc., Perkin Trans. 1 1992, 2725-2726. (10) Furukawa, J.; Kawabata, N.; Nishimura. J. Tetrahedron 1968, 24, 53-58. (11) Denmark, S.; O′Connor, S. P. J. Org. Chem. 1997, 62, 3390-3401. (12) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 86218624. (13) The diastereoselectivity was verified by independent synthesis of a mixture of cyclopropane diastereomers, which were distinguishable by gas chromatography (see Supporting Information). (14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 23, 3769-3772. Org. Lett., Vol. 3, No. 4, 2001
Scheme 4
Scheme 5
Reaction conditions: (a) Pd(PPh3)4, TlOEt, THF/H2O, rt; (b) DBU, MePh, 110 °C.
Reaction conditions: (a) p-BrC6H4COCl, pyr, CH2Cl2, 0 °C.
afford (-)-5 in 94% overall yield. The relative and absolute stereochemistry of the cyclopropane was verified by singlecrystal X-ray crystallographic analysis of the derived pbromobenzoate 15 (Scheme 4). Conversion of dibromide (-)-5 to the desired enyne alcohol 17 using the Stille coupling/elimination conditions developed by Shen4 was initially attempted with vinylstannanes 6a and 6b. This sequence produced the desired enynes in low yield (
